A? peptide (A?) accumulation is an important cause of AD, but may not be sufficient to cause cognitive deterioration. At diagnosis, neurotoxic pathways arguably downstream of A? may prove better or additional therapeutic targets. Recent data from our lab and others implicate soluble tau oligomers. Our data show that curcumin selectively reduces soluble tau dimers, and transgene dependent defects in heat shock proteins (HSPs), behavior, synapses and Fyn, a tau kinase implicated in Abeta toxicity. In contrast to curcumin, our data show that another polyphenol, fisetin, can reduce total tau and pS422 monomers. We propose to study the impact of fisetin, a CDK5 inhibitor and SIRT1 activator (fisetin) found in fruits (strawberries) an its synergism with curcumin on pTau species and synaptic and cognitive deficits in a tauopathy model, comparing efficacy to a novel tau aggregation inhibitor D-TKJ1VW. General Design: We will explore the relative impact of fisetin using a human wildtype tau huTauTg model relevant to sporadic AD (with or without A? infusion) on HSPs, autophagy, inflammation, synaptic proteins, fyn, cdk5,microtubule/ transport and mitochondria defects, behavior, tau oligomers and tau species. Objectives: Aim 1, To determine relative efficacy of fisetin versus a specific tau aggregation inhibitor in huTauTg mice with or without icv infusion of A?. Aim 2: To determine synergism between fisetin and curcumin in huTau Tg mice (with or without icv infusion of A?). Hypotheses: Interventions are used to clarify target engagement and significance of candidates (tau species, cdk5 or fyn activation, enhancing HSPs responses or autophagy) in correcting tauopathy, including identification of certain tau species that may be beneficial. 1. Fisetin will reduce tau transgene-associated hyperactivation of cdk5 but not fyn. 2. Fisetin reduces monomeric and insoluble ptau and increases unphosphorylated tau and stabilizes microtubules; however it does not result in reduction of oligomers, and only causes modest improvements in synaptic indices insufficient to improve cognition. 3. Unlike curcumin, fisetin wil not correct transgene-dependent heat shock responses. 4. Curcumin, but not fisetin will reduce total fyn, tau oligomers, the redistribution of CP13 ptau to dendrites as well as synaptic and cognitive deficits, but not NFT and insoluble tau. 5. Curcumin but not fisetin will stimulate Akt and downstream, p214 tau or MARK/ p262 tau. 6. Fisetin activates macroautophagic pathways via SIRT1 activation, while curcumin increases chaperone mediated microautophagy. 7. Bioavailable fisetin and curcumin will reduce different pathogenic species of ptau but act synergistically to reduce cognitive deficits, NFT, tau oligomers and insoluble tau and correct NR2B or PSD-95 receptor complex dysregulation in aged htau mice. 8. Anti-aggregation tau inhibitors but not the control peptide reduce pTau including oligomers but not pre-formed insoluble deposits or A? induced deficits and correct synaptic and cognitive but not HSPs defects. 9. A? +Tau models with tau-specific aggregate inhibition will help delineate A? vs. tau mechanisms and relative efficacies of the interventions. Potential Outcomes: Because fisetin directly inhibits CDK5, stabilizes microtubules and stimulates autophagic pathways, but has no effect on fyn, while curcumin reduces pathogenic fyn and selectively reduces tau oligomers, fisetin should differentially impact tau kinase/phosphatase balance, pTau and aggregates. Some but not all pTau species will correlate with NR2B/ PSD-95 receptor complex dysregulation and impact cognitive, synaptic and inflammatory endpoints. In summary, these studies are both mechanistic and translational, advancing knowledge in identification of the soluble toxic tau species and exclusion of non-toxic species, and protective tau clearance pathways. Completion of aims will move the field forward in demonstrating interrelationship between tau aggregation, synapto/neuro-protection, inflammation, autophagy and the HSPs.